ADC in Platinum-Resistant Ovarian Cancer

Transcript:Bradley J. Monk, MD: So we lived in a world of angiogenics. We live now in a world of PARP [poly ADP ribose polymerase]. We’re peeking around the corner for I/O [immune-oncology]. The next class of agents is antibody-drug conjugates. And the leading candidate for antibody-drug conjugates is this compound called mirvetuximab soravtansine—MIRV. I’ve been rehearsing.

Ursula A. Matulonis, MD: It’s the second word that’s a little harder.

Bradley J. Monk, MD: Thank you Mike, for being so passionate about this, both of you actually. Tell us about the mechanism of action and what this medication is, mirvetuximab soravtansine; tell us about it.

Michael J. Birrer, MD, PhD: I guess we classify it as a third-generation antibody-drug conjugate, and I emphasize that because antibody-drug conjugates have been around for a while, but [in] the early development of these there were a lot of false starts. And now we know that you need the antibody to have a high affinity for the antigen. The antigen needs to be expressed on the cancer cells and not anywhere else. And then you need to deliver a payload that’s really high potency, because once it gets into the cell and kills the tumor cell, it’ll then diffuse to the surrounding tumor cells and cause what’s known as a bystander effect.

Mirvetuximab [soravtansine] is a humanized antibody to the folate receptor alpha, which is really a terrific tumor marker. It’s highly expressed in high-grade serous ovarian cancer, maybe 60%-70% have very high expression, probably close to 100% have some expression. And you don’t find this protein expressed really in any other normal tissues. Maybe a little bit in the renal tubules.

And then the humanized antibody is linked through an important link that was developed over the last couple of years, to DB4, which is an anti-tubule agent. So that’s what it is, and it went through all the early testing, preclinical testing, and now we’re through a fair amount of early drug development trials, which showed a lot of activity with an acceptable toxicity profile.

Ursula A. Matulonis, MD: And importantly, that activity is in patients who are less heavily pretreated. So the phase 3 study that’s testing this agent against the kind of standard care of chemotherapy was built, based upon all of that early data.

Bradley J. Monk, MD: So let’s be clear. Drugs are brought to market these days through single-arm trials and accelerated approval. Just take olaparib and rucaparib as an example. Olaparib, 137 patients; rucaparib, 106. And then you say, well, you can’t really do that with MIRV because it doesn’t work that well in the highest unmet medical need where accelerated approval is an option. So now you’ve got to do a randomized trial, which takes time and money and effort, but at the same time is a little more definitive. So this FORWARD I trial, tell us what the eligibility is. I’ve tried to explain why that study had to be done, and it is done. It’s not reported, but tell us what it is.

Ursula A. Matulonis, MD: Along with what Mike just mentioned, it’s for patients who have high-grade serous carcinoma. It has a histology specific trial, and then paraffin-fixed tissue testing is done for expression of folate receptor alpha, and patients have to have a high expression of that. It’s done by an outside testing agency. And then patients were randomized.

Once one was not a blinded trial. Patients knew exactly what you’re getting to either rituximab alone versus….

Bradley J. Monk, MD: Platinum resistant.

Ursula A. Matulonis, MD: Thank you, platinum-resistant disease, correct. Platinum resistant not platinum sensitive, 1 to 3 prior lines, up to 3 prior lines, a less heavily pretreated patient population. Either MIRV alone or kind of a standard chemotherapy—either weekly paclitaxel, doxil, pegylated liposomal doxorubicin, or topotecan.

Bradley J. Monk, MD: It’s interesting because as you said, it’s open label. Many of our studies were blinded. But here, and I don’t know, I think we’ve all treated patients open label and we’ve seen tumors shrink and patients do well. So we’re excited about the results FORWARD I will report next year. Tell us about the toxicity now of this antibody-drug conjugate against the folate receptor.

Michael J. Birrer, MD, PhD: Let me go back to something before I answer that, what you said, because it was [a] really interesting observation. There was a lot of discussion in the company to do accelerated approval. And the initial data suggested, when the early studies were fully analyzed, it was felt that the response rate was not quite robust and that’s when we went to the 1 to 3, where the response rate is north of 45%. So we all remain very optimistic about this.

The toxicity profile is interesting. I think it’s got the typical ADC toxicities of antibody reactions. There’s some myelosuppression, some abdominal pain. But the novel finding, which turns out in retrospect is not that novel and that it happens with most ADCs, is that the patients can develop an ocular toxicity. And I always tell the story because it was my patient that showed up with this, where she called me on a Friday morning after we assumed that she was doing fine and said, “Dr. Birrer, I can’t see, I’m blind.” She wasn’t, but what happens is that….

Bradley J. Monk, MD: But she still couldn’t see.

Michael J. Birrer, MD, PhD: She couldn’t see anything. [She] developed these sort of pseudo cysts in her cornea and it interferes with her vision; so they get blurred vision. Fully reversible. We adjusted the ideal body weight, better dosed the drug, and now they get lubricating eye drops, and so the incidence of the vision loss is I think about 30% and it’s all grade 1 and grade 2. So I don’t see it as a big issue for FDA registration.

Bradley J. Monk, MD: So we eagerly await the results of FORWARD I, the randomized phase 3 trial, and 1 to 3 prior regimens; platinum-resistant; folate receptor high; single agent mirvetuximab soravtansine versus physician’s choice chemotherapy.

Transcript Edited for Clarity.